Cerebral malaria (CM) is caused by the interaction between Plasmodium falciparum infected erythrocytes (iRBC) and host brain endothelial cells. While available anti-malarial drugs are effective at clearing parasites from the blood, they do not have specific effects against cerebral malaria. Using an in vitro model, we have found that P. falciparum-iRBC induce the activation of ?-catenin in human brain microvascular endothelial cells (HBMEC), which results in their detachment from the substrate and disruption of inter-endothelial cell junctions. The activation of ?-catenin induces transcription of Tcf/LEF in the nucleus of HBMEC, which mediates the disruptions induced by P. falciparum-iRBC. We observed that treatments that inhibit the activation of ?-catenin, result in protection against P. falciparum-induced damage in endothelial cell monolayers in vitro and against experimental CM in mice. We propose that ?-catenin activation in brain endothelium is a central event in the development of CM pathology and that its inhibition can be explored for adjunct treatment against cerebral malaria. We have identified that the signaling induced by angiotensin II receptors (AT1 and AT2) modulates ?-catenin in endothelial cells and, as a result, the integrity of the inter-endothelial junctions and blood brain barrier integrity. Modulators of these receptors some of which are already approved or in clinical trials for use in humans, protect mice from experimental CM even when treatment is started after severe neurological symptoms are present. We intend to identify the P. falciparum-induced signaling pathway in endothelial cells leading to activation of ?- catenin and its inhibition by the AT2 signaling cascade to evaluate th importance of these pathways in human disease. Using a three-pronged approach with human brain microvascular endothelial cells in vitro, mouse models for cerebral malaria and endothelial cells from cerebral malaria patients, we intend to determine the role of these signaling pathways in human cerebral malaria. Our main goal is to understand P. falciparum- induced signaling in endothelial cells leading to the disruption of the blood brain barrier during cerebral malaria to develop therapies that, by inhibiting these signaling pathways, will specifically protect against cerebral malaria pathology. These findings may be relevant to the treatment of other brain hemorrhagic diseases, since more robust inter- endothelial junctions will result in a stronger blood brain barrier that would limit hemorrhagic pathology.